Potential of photoautotrophic microbial organisms in deciphering forensic issues.

In forensic pathology, solving the crime mystery of death due to drowning still remains a challenging issue. The amalgamation of autopsy findings and comparative study of diatoms recovered from the victim's body organs and suspected drowning site help to decipher the cause of death due to drowning or post-mortem immersion. Since the correct interpretation of the cause of death is an important criterion to provide justice to the victim, therefore, the main objective of our study is to throw light on the application of photoautotrophic micro-algal organisms, known as Diatoms, in solving seven cases of victims whose bodies were recovered from various water bodies of Himachal Pradesh, India. The diatom test was conducted by using reverse aqua regia solution (15 ml HNO3: 5 ml HCl) on the bone marrow extracted from the organs and water samples respectively. The informative outcomes of the experimental analysis demonstrated that the diatom test acts as a beneficial adjunct to solve drowning-related crimes where the exact cause of death remains hidden even after performing an autopsy of the victims. The protocol followed by the authors can be used conveniently to recover diatoms from bone marrow as well as from water samples. Our results showed that the maximum cases were of death due to accidental drowning but for one case of suicidal drowning in extremely cold water.

Photoplethysmography in postoperative monitoring of deep inferior epigastric perforator (DIEP) free flaps.

OBJECTIVE: Deep inferior epigastric perforator (DIEP) free flaps are widely used as a reconstruction option following mastectomy in breast cancer. During such cases partial tissue necrosis can occur due to the insufficient blood supply to the transplanted tissue site. Therefore, monitoring of flap perfusion and early detection of flap failure is a prerequisite to flap survival. There is a need to develop a non-invasive, easy to use, reproducible and inexpensive monitoring device to assess flap perfusion postoperatively. APPROACH: A three-wavelength reflective optical sensor and processing system based on the principle of photoplethysmography (PPG) has been developed to investigate blood volumetric changes and estimate free flap blood oxygen saturation continuously and non-invasively in DIEP free flaps in the postoperative period. The system was evaluated in 15 patients undergoing breast reconstructive surgery using DIEP free flap. Main results and Significance: Good quality red, infrared and green PPG signals were obtained in the postoperative period. Initial estimation of blood oxygen saturation values estimated from the free flap PPGs seem to be in broad agreement with the commercial finger pulse oximeter used in this study. This pilot study has demonstrated that PPG has the potential to be used as a monitoring technique in assessing free flap viability.

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.

Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.

BACKGROUND: Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel. METHODS: We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel. RESULTS: Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2-9.1), 4.0 (3.2-4.8), 4.1 (2.9-5.4) and 2.8 (2.5-3.2) months; median duration of enzalutamide was 9.1 (7.3-not reached), 4.7 (3.7-7.7), 5.4 (3.8-8.4) and 3.9 (3.0-4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7-16.5). 12-month OS was 78% (59-100%), 64% (45-90%), 77% (61-97%) and 51% (41-62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide. CONCLUSIONS: The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.

A phase I study of cabozantinib (XL184) in patients with renal cell cancer.

BACKGROUND: Cabozantinib targets tyrosine kinases including the hepatocyte growth factor receptor (MET) and vascular endothelial growth factor (VEGF) receptor 2, which are important drug targets in renal cell carcinoma (RCC). PATIENTS AND METHODS: This single-arm open-label phase I trial evaluated the safety and tolerability of cabozantinib in heavily pretreated patients with metastatic clear cell RCC. RESULTS: The study enrolled 25 RCC patients for whom standard therapy had failed. Patients received a median of two prior systemic agents, and most patients had previously received at least one VEGF pathway inhibiting therapy (22 patients [88%]). Common adverse events included fatigue, diarrhea, nausea, proteinuria, appetite decreased, palmar-plantar erythrodysesthesia, and vomiting. Partial response was reported in seven patients (28%). Median progression-free survival was 12.9 months, and median overall survival was 15.0 months. CONCLUSION: Cabozantinib demonstrates preliminary anti-tumor activity and a safety profile similar to that seen with other multitargeted VEGFR tyrosine kinase inhibitors in advanced RCC patients. Further evaluation of cabozantinib in RCC is warranted. ClinicalTrials.gov identifier: NCT01100619.

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC.

BACKGROUND: Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design. METHODS: Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria. RESULTS: In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months. CONCLUSIONS: Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.

Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials.

BACKGROUND: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Estimation of venous oxygenation saturation using the finger Photoplethysmograph (PPG) waveform.

In this study, finger photoplethysmograph data obtained from twelve patients undergoing cardiothoracic surgery were analyzed in order to estimate the venous saturation utilizing the modulations created by the positive pressure ventilation in the AC Photoplethysmograph (PPG) signals. The PPG signals were analyzed in the time-domain using a conventional pulse oximetry algorithm to produce estimations of arterial oxygen saturation. The instantaneous arterial and venous saturations were estimated by utilizing time-frequency analysis technique of Smoothed-pseudo Wigner-Ville Distribution (SPWVD). The results showed that there was no significant difference in the traditionally-derived (time-domain) arterial saturation and the instantaneous arterial saturation. However, the instantaneous venous saturation was found to be significantly lower than the time-domain estimated and instantaneous arterial saturation (P=<0.001).

Development of a reflectance photoplethysmographic sensor used for the assessment of free flap perfusion.

Monitoring of free flap perfusion and early identification of flap failure is an indispensable prerequisite for flap salvage. Although many methods of free flap monitoring are available, there is still no single reliable continuous non-invasive perfusion monitoring technique which will also assist in the early recognition of flap failure. In order to overcome the current technological limitations, we have developed a multi-wavelength photoplethysmographic (PPG) sensor and processing system to systematically investigate the perfusion mechanism in flaps used in reconstructive plastic microsurgery. The new prototype reflectance photoplethysmographic sensor was evaluated on three anaesthetized patients undergoing elective breast reconstructive (Deep Inferior Epigastric Perforator Flap) surgery. PPG signals were successfully obtained pre-operatively, intra-operatively and post-operatively. These preliminary results suggest that a PPG sensor may be a suitable method for evaluating the perfusion of free flap.

Concomitant renal cell carcinoma and chronic myelogenous leukemia: use of a targeted approach.

Numerous therapeutic options have been introduced for metastatic renal cell carcinoma (MRCC) in recent years, including monoclonal antibodies such as bevacizumab and small-molecule tyrosine kinase inhibitors such as sunitinib and sorafenib. Similarly, several other small-molecule inhibitors-including imatinib, dasatinib, and nilotinib-have been approved for the treatment of chronic myelogenous leukemia (CML). The combination of these targeted agents is an area of intense clinical investigation. Here, we describe a patient diagnosed with MRCC)while on imatinib therapy for cml. Treatment of this patient with the combination of bevacizumab and imatinib led to a 6-month period of stable disease, with no treatment-related adverse events. More extensive clinical exploration of this combination of agents may therefore be warranted.

Apoptotic surface delivery of K+ channels.

Apoptosis in cortical neurons requires efflux of cytoplasmic potassium mediated by a surge in Kv2.1 channel activity. Pharmacological blockade or molecular disruption of these channels in neurons prevents apoptotic cell death, while ectopic expression of Kv2.1 channels promotes apoptosis in non-neuronal cells. Here, we use a cysteine-containing mutant of Kv2.1 and a thiol-reactive covalent inhibitor to demonstrate that the increase in K+ current during apoptosis is due to de novo insertion of functional channels into the plasma membrane. Biotinylation experiments confirmed the delivery of additional Kv2.1 protein to the cell surface following an apoptotic stimulus. Finally, expression of botulinum neurotoxins that cleave syntaxin and synaptosome-associated protein of 25 kDa (SNAP-25) blocked upregulation of surface Kv2.1 channels in cortical neurons, suggesting that target soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins support proapoptotic delivery of K+ channels. These data indicate that trafficking of Kv2.1 channels to the plasma membrane causes the apoptotic surge in K+ current.

Carcinoma of the gall bladder presenting as dermatomyositis.

Dermatomyositis (DM), manifested as paraneoplastic syndrome, is not a very common clinical entity but its association with various internal malignancies is well-documented in literature. We present such a case of DM associated with characteristic skin lesions and subacute onset of proximal muscle weakness, acquired from a very rare malignancy like adenocarcinoma of gall bladder.

Hepatopulmonory syndrome--an uncommon and severe complication of certain liver diseases.

Hepatopulmonary syndrome (HPS) is charaterised by arterial hypoxaemia found mainly in association with chronic liver disease (most commonly cirrhosis of liver) but also rarely with acute liver diseases like fulminant hepatic failure or Budd-Chiari syndrome. The purpose of this article is to present an uncommon but grave complication mostly associated with cirrhosis of liver and to differentiate this entry from cyanotic heart diseases or certain lung conditions. Investigations include history and physical examination, certain biochemical tests, upper gastro-intestinal (GI) endoscopy, abdominal ultrasonography, liver biopsy and venacavography in appropriate cases. Finally, the suspected cases underwent arterial blood gas (ABG) analysis and contrast enhanced echocardiography (CEE) for confirmation of the diagnosis of HPS. Of the 123 cases of cirrhosis of liver, three cases of HPS (2.4%) were found-all of them being males. Also one male patient with inferior vena cava (IVC) obstruction amongst other causes presenting with HPS was encountered. As of now, no medical treatment has been proved to be useful and liver transplant remains the only hope for this disorder.

Uptake of isoflurane during prolonged clinical anaesthesia.

Recent evidence has suggested that the rate of uptake of inhalational anaesthetic is constant during maintenance of anaesthesia, contrary to the predictions of multi-compartment uptake models. We measured isoflurane uptake using a totally closed anaesthetic system during up to 10 h of stable anaesthesia for maxillo-facial surgery on 12 adult patients. Liquid isoflurane was injected into the system under computer control to produce an end tidal concentration of 1.3 MAC of isoflurane. Bench tests demonstrated that the leakage from the system was less than 8 microl min(-1), confirming that the rate of injection of isoflurane into the system was a close upper bound on the patients' uptake. Anaesthetic usage for a 70 kg patient was 0.44e(-0.51t)+0.044e(-0.013t)+0.058e(-0.00098t) ml min(-1) of liquid isoflurane, where t is duration of anaesthesia in minutes. There was a continuing reduction in anaesthetic requirement even at the end of the period of study that was statistically significant. These data do not support the notion that isoflurane uptake is constant during stable maintenance of anaesthesia but is compatible with the conventional multi-compartment model of anaesthetic uptake and distribution.